Effect of omega-3 fatty acid supplementation and added sugars in the diet on chemotherapy-induced cognitive deficits Abstract Women diagnosed with breast cancer (BC) comprises the largest group of cancer survivors in the United States. Chemotherapy used to treat BC has potentially toxic side effects in the brain, adversely affecting verbal fluency, memory and processing speed in up to 30% of women treated. The biological basis of chemotherapy induced cognitive dysfunction is poorly understood and no effective preventative strategies exist. Our preliminary data illustrate that chemotherapy increases oxidative stress, which in turn promotes neuroinflammation and cognitive changes in a mouse model; maintaining mice on high sucrose diets exacerbates the inflammation. In BC survivors, our data suggest that an unhealthy (i.e. high added sugar) diet increases systemic inflammation post-chemotherapy. Supplementing with omega-3 fatty acids (n-3 FAs) is a promising strategy to decrease inflammation and address life-altering cognitive side effects for several reasons: n-3 FAs reduce inflammatory cytokines and lipid peroxidation in rodent models, improve cognition in some older adults, and have established safety and tolerability with chemotherapy. However, high amounts of added sugars in the diet may interfere with the anti-inflammatory effects of n-3 FAs. The primary objective of this proposal is to use a randomized placebo controlled trial to determine the extent to which dietary supplementation with n-3 FAs reduces neuroinflammation and prevents cognitive decline in women receiving chemotherapy after BC surgery, and whether n-3 FAs are more effective in women whose usual diets are lower in added sugars. In addition, we will examine the mechanisms through which chemotherapy impairs cognitive performance and the potential of added sugars to modify the neuroprotective effects of n-3 FAs by including experiments using a translational mouse model that closely approximates the chemotherapy regimen commonly used to treat women with BC. We hypothesize that a low sugar/high n-3 FA diet will reduce neuroinflammation, decreasing inflammatory cytokines and activation of brain macrophages (microglia) in mice, which in turn will lessen chemotherapy-induced cognitive deficits. We further hypothesize that n-3 FA supplementation will decrease the cognitive side effects of chemotherapy in women with BC, and that the reduction in side effects will be greater in women who consume lower levels of added sugars in the diet. Understanding the mechanisms by which chemotherapy causes cognitive changes, the potential exacerbating role of added sugars, and intervening with n-3 FAs to alleviate these deficits are the necessary first steps in establishing an effective preventative strategy for chemotherapy-induced cognitive dysfunction, which could vastly improve quality of life for cancer survivors.